text:
Department of Health and Human Services
Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)
Components of Participating Organizations
National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov)
Title: The Role of Cellular Organelles in Alcohol-Induced Tissue Injury (R21)
Updates: The following updates relating to this announcement have been issued:
Announcement (PA) Number: PA-10-086
NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide.
This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).
A registration process is necessary before submission and applicants are highly encouraged to start the process at least four (4) weeks prior to the grant submission date. See Section IV.
Catalog of Federal Domestic Assistance Number(s)
Key Dates
Release/Posted Date: March 17, 2010
Opening Date: May 16, 2010 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): Not Applicable
NOTE: On-time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Due Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm
AIDS Application Due Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#AIDS.
Peer Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Council Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Earliest Anticipated Start Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Additional Information To Be Available Date (URL Activation Date): Not Applicable
Expiration Date: May 8, 2013
Dates for E.O. 12372
Not Applicable
Overview Content
Executive Summary
Table of Contents
Part I Overview Information
Part II Full Text of Announcement
Section I. Funding Opportunity Description
1. Research Objectives
Section II. Award Information
1. Mechanism of Support
2. Funds Available
Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2. Cost Sharing or Matching
3. Other-Special Eligibility Criteria
Section IV. Application and Submission Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Submission, Review, and Anticipated Start Dates
1. Letter of Intent
B. Submitting an Application Electronically to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements
Section V. Application Review Information
1. Criteria
2. Review and Selection Process
3. Anticipated Announcement and Award Dates
Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting
Section VII. Agency Contacts
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/Grants Management Contact(s)
Section VIII. Other Information - Required Federal Citations
Part II - Full Text of Announcement
Section I. Funding Opportunity Description
Research Objectives
Excessive acute or chronic alcohol consumption often leads to various medical disorders, resulting in enormous economic and public health burdens to our society. These medical disorders include alcoholic hepatitis and cirrhosis, pancreatitis, cardiomyopathy, immune system defects, and fetal abnormalities. Alcohol's effects on these organs often impact the structure and function of mitochondria, which play a central role in cellular energy metabolism, production of reactive oxygen species (ROS), and programmed cell death. Altered mitochondrial function, apoptosis, or excessive oxidative stress may contribute to the pathogenesis of many metabolic diseases, and aging-associated dysfunction. It has been known that alcohol can affect the structure and function of mitochondria and endoplasmic reticulum (ER). However, little is known about the underlying mechanisms of these effects, and the relationships between alcohol-induced dysfunctions of mitochondria, ER, or other cellular organelles in causing tissue damage. Taking advantage of recent technological advances such as genomics, proteomics, and imaging, studies on mitochondria, ER, and other cellular organelles may shed light on various mechanisms and provide new avenues for the diagnosis and treatment of alcohol-induced tissue injury.
The mitochondrion is central to energy production in the cell, and consists of two membranes of phospholipid bilayer, dividing mitochondrion into two compartments, the inter-membrane space and matrix. The outer membrane is permeable to ions and small molecules (< 5 KD) because of large pores made of the trans-membrane mitochondrial protein, porin (also known as Voltage-Dependent Anion Channel, VDAC), although the open/closed state of mitochondrial porin may be regulated. The inner mitochondrial membrane is less permeable and, therefore, serves as an electrical insulator and chemical barrier to separate the matrix from the cytosolic environment, and maintains a proton gradient necessary for proper mitochondrial energy production. Mitochondria contain a range of enzymes involved in the metabolism of carbohydrates, lipids, amino acids, and urea, and in the biosynthesis of heme. While most of the citric acid cycle and fatty acid oxidation take place in the mitochondrial matrix, ATP is generated by oxidative phosphorylation driven by the proton electrochemical gradient generated through the electron transport chain in the inner mitochondrial membrane. The number of mitochondria in each cell or tissue varies widely, depending on cellular energy demands. Each mitochondrion contains multiple copies of a small circular genome that encodes only 37 genes in mammals. Thirteen of these 37 genes encode mitochondrial proteins essential for the respiratory chain. The remainder encode ribosomal and transfer RNAs, which are important for mitochondrial protein synthesis. Individual mitochondrial genomes appear to replicate at random throughout cell cycle. Mitochondria are not generated de novo. Rather, their biogenesis can happen at any point in the cell cycle through fission of mature mitochondria. The mitochondrial fusion and fission can generate a more integrated or more distributed mitochondrial network. It is estimated that mammalian mitochondria contain approximately 1500 proteins. With only 13 proteins encoded by the mitochondrial genome, more than 99% of the mitochondrial proteins are encoded by the nuclear genome and transported to the mitochondria by highly regulated mechanisms. The application of proteomics has been a valuable approach to study alcohol-induced protein changes in mitochondria. In an animal model of chronic ethanol exposure, quantitative changes in 43 mitochondrial proteins were demonstrated.
Despite extensive studies on a limited number of mitochondrial proteins, very little is known about the majority of mitochondrial proteins in terms of their function, regulation, and relevance to human disease.
Both acute and chronic alcohol intake affect the structure and function of mitochondria in a variety of tissues in humans and animal models. Alcohol's effects on mitochondria were first observed as morphological changes, viz., mitochondrial enlargements, shape distortions, and disruption of cristae. The effects of alcohol on mitochondrial function that accompany structural alterations have only been partially studied. Ethanol exposure increases NADH level, reduces the synthesis of ATP by inhibiting the electron transport chain and oxidative phosphorylation, and decreases fatty acid oxidation. Ethanol also increases the levels of malonyl-CoA by activating acetyl-CoA carboxylase, thus inhibiting fatty acid transport into the mitochondrion and increasing fatty acid synthesis, thus contributing to fatty liver. In addition, ethanol alters mitochondrial protein synthesis and damages mitochondrial DNA.
Mitochondria are the major source for reactive oxygen species (ROS) through cellular respiration, and alcohol metabolism further increases ROS production by increasing the the levels of NADH. ROS is also produced by cytochrome P450 2E1 (CYP2E1) which metabolizes alcohol at high concentrations. Although most CYP2E1 is localized outside the mitochondria, some CYP2E1 is expressed in the mitochondrial inner membrane. Chronic alcohol exposure induces both microsomal and mitochondrial CYP2E1, and results in a greater increase of the enzyme in mitochondria (69%) than in microsomes (43%). In addition to the production of ROS, oxidation of alcohol through alcohol dehydrogenase (ADH) or CYP2E1 generates acetaldehyde. Acetaldehyde is a highly reactive and toxic metabolite that is oxidized predominantly through the low-Km mitochondrial aldehyde dehydrogenase (ALDH), and may contribute to mitochondrial damage. Furthermore, alcohol reduces intracellular antioxidant defense mechanisms, by reducing mitochondrial glutathione. These processes may also affect cell fate through oxidative stress-related signaling pathways. Oxidative damage to the mitochondria can alter membrane permeability, membrane potential, and calcium homeostasis, and causes inappropriate activation of the mitochondrial permeability transition. This damage, in turn, causes mitochondrial swelling and cristae fracture, leading to cytochrome c release and further ROS production, and eventually apoptosis through activation of the caspase signaling cascade. Accumulation of ROS such as superoxide, hydrogen peroxide, and hydroxyl radicals, along with a compromised antioxidant capacity, can also affect other cellular functions by damaging organelles other than mitochondria. In addition, a variety of cellular stress signaling pathways that integrate mitochondrial function with other parts of the cell can affect the sensitivity of mitochondria to ROS and other damaging agents and help determine cell fate. An emerging area of research is the regulation of mitochondrial function and cellular energetics by peroxisome proliferator-activated receptors (PPAR), especially PPAR? coactivator-1 (PGC-1) family of transcriptional coactivators, in particular PGC-1?. PPAR receptors appear to have a considerable role in the regulation of lipid metabolism, glucose homeostasis, and cellular differentiation. PGC-1 interacts with both nuclear receptor and non-nuclear receptor transcription factors to regulate mitochondrial biogenesis and increase mitochondrial energy production. Recently, PGC-1? has been shown to control the production of ROS, thereby maintaining proper mitochondrial function. PGC-1 is highly responsive to a variety of environmental cues and regulates metabolic pathways and biological processes in a tissue-specific manner. Although alcohol consumption alters SIRT1, which influences PGC-1a, little is known about the actions of alcohol on PPAR and its coactivators, and the subsequent contributions to alcohol-induced tissue injury.
The integrity of the mitochondrial genome and fidelity of its replication, transcription, and translation are critical for the function of the mitochondria. Mutations in the mitochondrial genome can cause ATP insufficiency, overproduction of reactive oxygen species, and increased sensitivity to apoptosis, leading to a variety of human disorders. Despite its importance for the function of mitochondria and the cell as a whole, the mitochondrial genome is relatively prone to damage. Whereas nuclear genome is protected by its associated histone proteins and a sophisticated DNA repair system, only one repair mechanism has been shown to exist in mitochondria. The lack of protective histone and reduced fidelity of DNA replication and DNA repair make mitochondrial genome more sensitive to free radical attack or other DNA damaging agents notably acetaldehyde. As a result, the mutation rate of the mitochondria genome in mammals is 10 to 20 times greater than that of the nuclear genome. Ethanol can cause overproduction of ROS, and acetaldehyde, the first metabolite of ethanol, can form DNA adducts and cause sequence alteration of the DNA. Thus, chronic alcohol consumption could cause mutations in mitochondria DNA. Accumulation in mitochondria of such mutations could lead to the impairment of mitochondrial function and contribute to alcohol-induced disorders. Furthermore, variations in mitochondrial genes among different people could also contribute to their susceptibility or resistance to alcohol-induced tissue injury. Examination of mitochondrial DNA for mutations or variations in human or animal models after chronic exposure of ethanol should yield some insightful answers to this question.
Endoplasmic Reticulum (ER)
The ER is an essential organelle that consists of a membranous network of branching tubules and flattened sacs, which extends throughout the cytoplasm of the cell and connects with the nuclear envelope. Functioning as protein folding machinery, the ER provides a specialized environment for the production, folding, assembly, and posttranslational modification of numerous soluble proteins and membrane proteins. The correctly folded proteins reach various cellular locations or are transported to the surface of the cell, whereas unfolded or misfolded proteins are retained in the ER and rapidly degraded by the ubiquin pathways after being translocated to the cytoplasm by the ER-associated degradation (ERAD) machinery. Steroids, cholesterol, and other lipids are also primarily synthesized in the ER. The ER is also a storing site for Ca2+, which level can reach several thousand-fold greater than that in cytosol. Ca2+ can be released in a controlled and dynamic fashion in response to growth factors, hormones, cellular energy levels, and redox status. A drastic increase in protein synthesis and the demand for their folding and modification may exceed the capacity of the ER and ERAD machinery. This condition, or the perturbation of the ER environment such as alterations in redox state or Ca2+ levels, can cause the accumulation of unfolded or misfolded proteins in ER, a condition called ER stress. An unfolded protein response (UPR) mechanism has been evolved in eukaryote cells to cope with ER stress and safeguard the fidelity of protein folding through transcriptional and translational regulations of a series of signaling pathways. Depending on the physiological conditions, the UPR could be protective of ER stress or detrimental to the cell, leading to apoptosis.
The ER is an important sensor for cellular stress, and is involved in many physiological processes, such as inflammation, oxidative stress, and metabolism. ER dysfunction has also been implicated in many human diseases, such as obesity, diabetes, and atherosclerosis. Recently, studies also suggest that the ER may play an important role in alcohol-induced tissue injury. The ER stress response pathways have been demonstrated to be critical for both alcohol-induced liver disease and nonalcoholic liver disease. HCV or HBV infections could cause heavy overload of ER, resulting in ER stress, which may contribute to the accelerated progression of liver disease. ER stress has been shown to be associated with lipid production by promoting the activation of transcription factors such as sterol regulatory element-binding proteins SREBP-1c and SREBP-2. Alcoholic patients have increased plasma homocysteine level. Studies in animal models have shown that hyperhomocysteinemia caused by heavy alcohol intake is associated with ER stress, and leads to fatty liver through the activation of SREBPs. Homocysteine can disrupt disulphide bond formation, leading to the misfolding of ER proteins and causes ER stress. Betaine, a methyl donor that converts homocysteine to methionine, can relieve ER stress in hyperhomocysteinemic mice. In addition to homocysteine, excessive amount of glucose, cholesterol, non-esterified fatty acids, cytokines, and some neurotransmitters has also been shown to cause ER stress. ER dysfunction has been shown to be associated with metabolic disorders such as insulin resistance. The ER is an important site for the regulation of cellular metabolism since it controls biosynthesis of triglyceride and cholesterol, as well as the synthesis, correct folding, and secretion of proteins involved in metabolism. Alcohol, or its first metabolite acetaldehyde, affects many aspects of cellular metabolism, and induces ER stress. It is likely that many of alcohol's effects on metabolism may be mediated through ER-related pathways.
In addition, some biological pathways closely related to alcohol's actions are now known to be involved in, or affected by, the function of ER, such as oxidative stress, inflammatory cytokines like TNF? and IL-6, NF?B, MAPK, and redox state. Correct folding of proteins in the ER result in the formation of intra- and inter-molecular disulphide bonds, which requires energy and oxidizing conditions, and consumes reduced glutathione. Therefore, ER stress can generate and accumulate intracellular reactive oxygen species (ROS). Conversely, the oxidative state in the ER can affect protein folding and other ER functions. ER stress can cause the leakage of calcium, which accumulates in the mitochondrial matrix. This increase in calcium levels can depolarize the inner mitochondrial membrane and affect the electron transport chain, leading to increased production of ROS. In turn, mitochondrial ROS can exacerbate calcium leakage from ER by causing more protein misfolding and sensitizing calcium-release channels in the ER. ROS and the released calcium can then trigger many signaling pathways and lead to various cellular dysfunction. These functional interactions in signaling and metabolism between mitochondria and ER may be also involved in alcohol's action. Further studies on these interactions will help decipher the underlying mechanisms of alcohol-induced tissue injury.
Other Cellular Organelles
Other cellular organelles, such as Golgi apparatus, endosome, and peroxisome, may also play an important role in alcohol-induced tissue injury. Ethanol, competing with water for its hydrogen bonding capability, can target lipids, proteins, and carbohydrates on membrane surfaces and cause changes in conformation or chemical properties. The cellular organelles with relatively low water content such as Goligi are especially vulnerable to the effects of ethanol. For example, a recent study has shown that alcohol prevent the transport of Sonic Hedgehog (Shh) protein from the Golgi to the plasma membrane, resulting in a deficiency of Shh ligand secretion into the extracellular matrix. In addition, Golgi apparatus is involved in the secretion of VLDL. Studies of Golgi and other cellular organelles for their roles in mediating alcohol's action may provide new perspective in understanding the mechanisms of alcohol-induced tissue injury.
In addition to its effects on DNA, synthesis and folding of protein, metabolism, and cellular transport, it is important to understand how alcohol affects homeostasis and interactions of cellular organelles. The ultimate goal of this FOA is to decipher the molecular events and interconnecting metabolic and signaling networks affecting cellular organelles that result in alcohol-induced tissue injury. A better understanding of the role of cellular organelles in alcohol-induced tissue injury may provide new avenues for diagnostic and therapeutic interventions.
Research Objectives:
The major focus of this FOA is three-fold: (1) The effects of alcohol on the structure and function of cellular organelles; (2) The role of cellular organelles and related pathways in alcohol-induced tissue injury; (3) The development of cellular organelle-related biomarkers or therapeutic targets for alcohol-induced tissue injury. Studies using human samples, animal models, tissue culture cells, or in vitro biochemical systems are considered to be appropriate in response to this FOA.
Appropriate topics include but are not limited to:
The evolution and vitality of the biomedical sciences require a constant infusion of new ideas, techniques, and points of view. These may differ substantially from current thinking or practice and may not yet be supported by substantial preliminary data. By using the R21 mechanism, the NIH seeks to foster the introduction of novel scientific ideas, model systems, tools, agents, targets, and technologies that have the potential to substantially advance biomedical research.
The R21 mechanism is intended to encourage new exploratory and developmental research projects. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. Another example could include the unique and innovative use of an existing methodology to explore a new scientific area. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research.
Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well-established area, will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications. Projects of limited cost or scope that use widely accepted approaches and methods within well established fields are better suited for the R03 small grant mechanism. Information on the R03 program can be found at https://grants.nih.gov/grants/funding/r03.htm.
See Section VIII, Other Information
- Required Federal Citations, for policies related
to this announcement.
Section II. Award Information
Mechanism of Support
This FOA will use the NIH Exploratory/Developmental Research Grant (R21) award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.
This FOA uses "Just-in-Time" information concepts see SF424 (R&R) Application Guide). It also uses modular as well as non-modular budget formats (see the "Modular Applications and Awards" section of the NIH Grants Policy Statement. Specifically, if you are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, "Modular Budget Component," of the Application Guide).
U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component.
2. Funds Available
Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the Institutes and Centers (ICs) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.
The total project period for an application submitted in response to this funding opportunity may not exceed 2 years. Although the size of award may vary with the scope of research proposed, it is expected that applications will stay within the budgetary guidelines for an exploratory/developmental project; direct costs are limited to $275,000 over an R21 two-year period, with no more than $200,000 in direct costs allowed in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined two-year award period. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.
Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.
Section III. Eligibility Information
Eligible Applicants
1.A. Eligible Institutions
The following organizations/institutions are eligible to apply:
1.B. Eligible Individuals
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application for projects that require a "team science" approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at https://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH electronic Research Administration (eRA) Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).
The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering the multiple PD/PI option, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see https://grants.nih.gov/grants/multi_pi.
2. Cost Sharing or
This program does not require cost sharing as defined in the current NIH Grants Policy Statement.
3. Other-Special Eligibility Criteria
Number of Applications. Applicants may submit more than one application, provided that each application is scientifically distinct.
Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous peer review critique (Summary Statement). Beginning with applications intended for the January 25, 2009 official submission due date, all original new applications (i.e., never submitted) and competing renewal applications are permitted only a single amendment (A1). See https://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-003.html and NOT-OD-09-016. Original new and competing renewal applications that were submitted prior to January 25, 2009 are permitted two amendments (A1 and A2). For these "grandfathered" applications, NIH expects that any A2 will be submitted no later than January 7, 2011, and NIH will not accept A2 applications after that date.
Renewals. Exploratory/developmental grant support is for new projects only; competing renewal (formerly "competing continuation") applications will not be accepted.
Section IV. Application and Submission Information
download a SF424 (R&R) Application Package and SF424 (R&R) Application
Guide for completing the SF424 (R&R) forms for this FOA, use the "Apply for
Grant Electronically" button in this FOA or link to http://www.grants.gov/Apply/ and follow
the directions provided on that Web site.
Appropriate registrations with Grants.gov and eRA Commons must be completed on or before the due date in order to successfully submit an application. Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered with both Grants.gov and the Commons. All registrations must be complete by the submission deadline for the application to be considered "on-time" (see 3.C.1 for more information about on-time submission).
A one-time registration is required for institutions/organizations at both:
PDs/PIs should work with their institutions/organizations to make sure they are registered in the NIH eRA Commons.
Several additional separate actions are required before an applicant can submit an electronic application, as follows:
1) Organizational/Institutional Registration in Grants.gov/Get Registered.
2) Organizational/Institutional Registration in the eRA Commons
3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.
Note: The registration process is not sequential. Applicants should begin the registration processes for both Grants.gov and eRA Commons as soon as their organization has obtained a DUNS number. Only one DUNS number is required and the same DUNS number must be referenced when completing Grants.gov registration, eRA Commons registration and the SF424 (R&R) forms.
Request Application Information
Applicants must download the SF424 (R&R) application forms and SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.
Only the forms package directly attached to a specific FOA can be used. You
will not be able to use any other SF424 (R&R) forms (e.g., sample forms,
forms from another FOA), although some of the "Attachment" files may
be useable for more than one FOA.
For further assistance, contact GrantsInfo -- Telephone 301-710-0267, Email: email@example.com.
Telecommunications for the hearing impaired: TTY 301-451-5936.
2. Content and Form of Application Submission
Prepare all applications using the SF424 (R&R) application forms for this FOA through Grants.gov/Apply and in accordance with the SF424 (R&R) Application Guide (https://grants.nih.gov/grants/funding/424/index.htm).
The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the "Credential" log-in field of the "Research & Related Senior/Key Person Profile" component must contain the PD/PI's assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see "Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications."
The SF424 (R&R) application is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY will include all applicable components, required and optional. A completed application in response to this FOA will include the following components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6. regarding appropriate required budget component.)
Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form
Organizations (Non-domestic [non-U.S.] Entities)
NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: https://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.
Applications from Foreign organizations must:
Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States (U.S.) or that augment existing U.S. resources.
Applications with Multiple PDs/PIs
When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact" PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.
Information for the Contact PD/PI should be entered on the SF424 (R&R) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of "PD/PI." Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the "Credential" field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected.
Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, the Research Plan section and the Multiple PD/PI Leadership Plan must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.
If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award (NoA).
Applications Involving a Single Institution
When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.
Applications Involving Multiple Institutions
When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form.
When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only. Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 5.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.
3. Submission Dates and Times
See Section IV.3.A for
3.A. Submission, Review, and Anticipated Start Dates
Opening Date: May 16, 2010 (Earliest date an application may be submitted to Grants.gov)
Letter of Intent Receipt Date(s): Not Applicable
Application Due Date(s): Standard dates apply, please see https://grants.nih.gov/grants/funding/submissionschedule.htm
AIDS Application Due Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#AIDS
Peer Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Council Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Earliest Anticipated Start Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
3.A.1. Letter of Intent
A letter of intent is not required for the funding opportunity.
3.B. Submitting an Application Electronically to the
To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/Apply and follow Steps 1-4. Note: Applications must only be submitted electronically. PAPER APPLICATIONS WILL NOT BE ACCEPTED. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.
3.C. Application Processing
3.C.1 Submitting On-Time
Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due date(s) and time, the application may be delayed in the review process or not reviewed. All applications must meet the following criteria to be considered "on-time":
Please visit http://era.nih.gov/electronicReceipt/app_help.htm for detailed information on what to do if Grants.gov or eRA system issues threaten your ability to submit on time.
Submission to Grants.gov is not the last step – applicants must follow their application through to the eRA Commons to check for errors and warnings and view their assembled application!
3.C.2 Two Day Window to Correct eRA Identified Errors/Warnings
IMPORTANT NOTE! NIH has eliminated the error correction window for due dates of January 25, 2011 and beyond. As of January 25, all corrections must be complete by the due date for an application to be considered on-time. See NOT-OD-10-123.
Once an application package has been successfully submitted through Grants.gov, NIH provides applicants a two day error correction window to correct any eRA identified errors or warnings before a final assembled application is created in the eRA Commons. The standard error correction window is two (2) business days, beginning the day after the submission deadline and excluding weekends and standard federal holidays. All errors must be corrected to successfully complete the submission process. Warnings will not prevent the application from completing the submission process.
Please note that the following caveats apply:
3.C.3 Viewing an Application in the eRA Commons
Once any eRA identified errors have been addressed and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two weekdays (Monday – Friday, excluding Federal holidays) to view the assembled application before it automatically moves forward to NIH for further processing.
Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed.
There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR/SO receives the Grants.gov acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.
Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on the application status in the Commons.
The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. However, the NIH will accept a resubmission application, but such application must include an Introduction addressing the critique from the previous review.
4. Intergovernmental Review
This initiative is not subject to intergovernmental review.
5. Funding Restrictions
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.
The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See the NIH Grants Policy Statement.
6. Other Submission Requirements
PD/PI Credential (e.g., Agency Login)
The NIH requires the PD/PI to fill in his/her Commons User ID in the "PROFILE – Project Director/Principal Investigator" section, "Credential" log-in field of the "Research & Related Senior/Key Person Profile" component. The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see "Registration FAQs – Important Tips -- Electronic Submission of Grant Applications."
Organizational DUNS
The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see "Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications."
PHS398 Research Plan Component Sections
All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following requirements for R21 applications:
Budget Component
U.S. applicants submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs) must use the PHS398 Modular Budget component.
U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component.
R21 applications will use the modular as well as non-modular budget formats and "Just-in-Time" information concepts, with direct costs requested in $25,000 modules, up to the total direct costs limitation of $275,000 over an R21 two-year period. No more than $200,000 in direct costs will be allowed in any single year. All foreign applicants must complete and submit budget requests using the Research & Related Budget component.
Appendix Materials
Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See https://grants.nih.gov/grants/funding/424/index.htm). Also see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html.
Do not use the Appendix to circumvent the page limitations. An application that does not comply with the required page limitations may be delayed in the review process.Resource Sharing Plan(s)
NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in the Resource Sharing section of the application (see https://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm).
(a) Data Sharing Plan: Not Applicable
(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.
(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (e.g., blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (go to NOT-OD-07-088, and https://grants.nih.gov/grants/gwas/.)
Foreign Applications (Non-domestic (non-U.S.) Entity)
Indicate how the proposed project has specific relevance to the mission and objectives of the NIH/IC and has the potential for significantly advancing the health sciences in the United States.
Section V. Application Review Information
1. Criteria
Only the review criteria described below will be considered in the review process.
2. Review and Selection Process
Review Process
Applications submitted for this funding opportunity will be assigned to the ICs on the basis of established Public Health Service (PHS) referral guidelines.
Applications that are complete will be evaluated for scientific and technical merit by (an) appropriate scientific review group(s) in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/) using the review criteria stated below.
As part of the initial merit review, all applications will:
The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.
The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
Overall Impact. Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five scored review criteria, and additional review criteria (as applicable for the project proposed).
Scored Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Significance. Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Innovation. Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?
Environment. Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
Additional Review Criteria
As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.
Protections for Human Subjects. For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials.
Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.
Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information, see https://grants.nih.gov/grants/olaw/VASchecklist.pdf.
Biohazards. Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Resubmission Applications. When reviewing a Resubmission application (formerly called an amended application), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.
Revision Applications. When reviewing a Revision application (formerly called a competing supplement application), the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.
Additional Review Considerations
As applicable for the project proposed, reviewers will address each of the following items, but will not give scores for these items and should not consider them in providing an overall impact/priority score.
Select Agents Research. Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Applications from Foreign Organizations. As applicable for the FOA or submitted application, reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
Resource Sharing Plans. Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (Not Applicable); 2) Sharing Model Organisms (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).
Budget and Period Support. Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Selection Process
Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:
Anticipated Announcement and Award Dates
Not Applicable
Section VI. Award Administration Information
Award Notices
After the peer review of the application is completed, the PD/PI will be able to access his/her Summary Statement (written critique) via the NIH eRA Commons.
the application is under consideration for funding, NIH will request
"just-in-time" information from the applicant. For details,
applicants may refer to the NIH
Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards,
Subpart A: General.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.
Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Section IV.5., "Funding Restrictions."
2. Administrative and National Policy Requirements
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities.
When multiple years are involved, awardees will be required to submit the Non-Competing Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.
A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.
We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research (program), peer review, and financial or grants management issues:
Scientific/Research Contacts:
Max Guo, Ph.D.
Division of Metabolism and Health Effects
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health, DHHS
5635 Fishers Lane, Room 2037
Bethesda, MD 20892-9304
Telephone: 301-443-0639
Fax: 301-594-0673
Email: email@example.com
2. Peer Review Contacts:
Not Applicable
3. Financial or Grants
Management Contacts:
Judy Fox
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health, DHHS
5635 Fishers Lane MSC 9304 Room 3023
Bethesda, MD 20892-9304
[For express mail use: Rockville, MD 20852-1705]
Telephone: 301-443-4704
Email: firstname.lastname@example.com
Section VIII. Other Information
Required Federal Citations
Use of Animals
in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (https://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (https://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.
Human Subjects
Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).
Data and Safety
Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants ("NIH Policy for Data and Safety Monitoring," NIH Guide for Grants and Contracts, https://grants.nih.gov/grants/guide/notice-files/not98-084.html).
Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (https://grants.nih.gov/grants/policy/data_sharing). Investigators should seek guidance from their institutions, on issues related to institutional policies and local institutional review board (IRB) rules, as well as local, State and Federal laws and regulations, including the Privacy Rule.
Policy for Genome-Wide
Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see https://grants.nih.gov/grants/gwas/.
Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see https://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh-Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.
Access to Research Data through the Freedom of
Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are: (1) first produced in a project that is supported in whole or in part with Federal funds; and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.
Inclusion of Women And Minorities in Clinical
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research" (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R) application; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.
Inclusion of Children as Participants in Clinical
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.
All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (https://grants.nih.gov/grants/funding/children/children.htm).
Required Education on the Protection of Human Subject
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
Human Embryonic Stem Cells (hESC):
Criteria for Federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-116.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.
NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators funded by the NIH must submit or have submitted for them to the National Library of Medicine's PubMed Central (see http://www.pubmedcentral.nih.gov/), an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. The NIH Public Access Policy is available at (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html). For more information, see the Public Access webpage at http://publicaccess.nih.gov/.
Standards for Privacy of Individually Identifiable
Health Information:
The Department of Health and Human Services (HHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the HHS Office for Civil Rights (OCR).
Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.
in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.
People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.
Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov/.
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ON FEBRUARY 10TH, 1982, in a room full of designers and engineers drinking champagne and eating cake, Steve Jobs called out the names of Apple's Macintosh team. And one by one, beginning with motherboard engineer Burrell Smith, they signed their names to a large sheet of paper.
These 47 signatures—some in perfect script, others loopy and illegible, a few just hastily printed—would soon be inscribed on the inside of every Macintosh, etched into the hard plastic case. According to former engineer Andy Hertzfeld, whose signature is on that paper and whose business card during his time at Apple read "Software Wizard," this was a natural course of events. "Since the Macintosh team were artists," he wrote on his blog Folklore.org, "it was only appropriate that we sign our work."
Yet what Dye seems most fascinated by is one of the Apple Watch's faces, called Motion, which you can set to show a flower blooming. Each time you raise your wrist, you'll see a different color, a different flower. This is not CGI. It's photography.
"We shot all this stuff," Dye says, "the butterflies and the jellyfish and the flowers for the motion face, it's all in-camera. And so the flowers were shot blooming over time. I think the longest one took us 285 hours, and over 24,000 shots."
He flips a few pages further into the making-of book, onto the first of several full-page spreads with gorgeous photos of jellyfish. There's no obvious reason to have a jellyfish watch face. Dye just loves the way they look. "We thought that there was something beautiful about jellyfish, in this sort of space-y, alien, abstract sort of way," he says. But they didn't just visit the Monterey Bay Aquarium with an underwater camera. They built a tank in their studio, and shot a variety of species at 300 frames-per-second on incredibly high-end slow-motion Phantom cameras. Then they shrunk the resulting 4096 x 2304 images to fit the Watch's screen, which is less than a tenth the size. Now, "when you look at the Motion face of the jellyfish, no reasonable person can see that level of detail," Dye says. "And yet to us it's really important to get those details right."
The Watch's faces are littered with such details. The Mickey Mouse face, which is an explicit update on the 1933 Mickey Mouse Watch from Ingersoll, was particularly complex. Select this face, and watch Mickey's toe tap once per second, in perfect time. Line up a bunch of watches, Dye says, and they'll all tap at exactly the same time. There's no reason to point out that almost no one will ever fact-check this claim—he doesn't care. He did it for the same reason Jony Ive has taken to personally designing the internals of the Mac. Details matter.
The Astronomy watch face is another of Dye's favorites: it gives you a view of the Earth as if you were floating peacefully above it. Spin the Digital Crown and you see moon phases, the Earth's rotation, and even the solar system. It's a riff on the oldest method of telling the time just with digital stars and planets instead of those far-away real ones.
Dye points out the subtlety of this face. "When you tap on the Earth and fly over the moon: We worked really hard with our engineering team to make sure the path you take from your actual position on the Earth to where the moon is and seeing its phase, is true to the actual position of the Earth relative to the moon."
Apple employees often use the word "inevitable" to describe their work. When Dye uses it, it's self-deprecating, as if to say: 'this was always the right answer, but it took us a while to figure that out.' It's true of even seemingly simple things, he says, like the concentric circles the Watch uses to display your fitness goals.
"I couldn't tell you from a design perspective the number of iterations we did on those three rings." The human interface team wanted to make it easy to see progress and activity for the day, but also to make you want to hit your goals. "We spent a year, and did far more studies… enough studies to kind of fill this wall, probably," he says, gesturing to the giant glass walls of Apple's Caffe Macs cafeteria. "Different ways that, at a glance, someone could understand that information, and easily assess where they're at in their day, and hopefully in a really simple and visceral way feel like they accomplished something when they fill them up." They arrived at three circles because there's just something about a not-quite-complete circle that drives you just crazy enough to take those last 400 steps.


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CHARLESTON, South Carolina (Reuters) - Former South Carolina Governor Mark Sanford, seeking political redemption after a sex scandal, won a runoff on Tuesday to become the Republican nominee for an open seat in the House of Representatives, setting up a May showdown against the sister of prominent political satirist Stephen Colbert.
Sanford beat his Republican opponent, Charleston attorney and former Marine Curtis Bostic, 57 percent to 43 percent, official results showed. He now faces Democratic nominee Elizabeth Colbert Busch in the Republican-leaning coastal congressional district's special election on May 7.
While serving as governor in 2009, Sanford disappeared for almost a week, telling aides he was hiking the Appalachian Trail when he was, in fact, visiting his mistress in Argentina.
After the news of Sanford's affair broke, his wife divorced him, he paid more than $70,000 in ethics fines and he was censured by the state legislature, though he served out the remainder of his term as governor. He is now engaged to marry the woman, Argentine journalist Maria Belen Chapur, who attended Sanford's victory celebration on Tuesday.
Colbert Busch's campaign said in a statement that "Sanford simply has the wrong values for our community," adding: "The families of this district need a representative who they can trust."
Sanford, who previously served in the House before being elected governor, said in a statement that his views and those of Colbert Busch "couldn't be more at odds with one another."
"My record is one of cutting debt, eliminating deficits, reducing taxes and working to make sure (businesses) are more competitive. On the other side, we have more of the same of what has gotten our country into the mess that it's in - a belief in government and government spending on things like the stimulus are a cure to all ills," Sanford added.
Both Republican candidates touted their fiscal conservatism and their opposition to same-sex marriage.
South Carolina Republican Party Chairman Chad Connelly described Colbert Busch as an overpaid "liberal darling" out of touch with local values.
The district, which was redrawn after the 2010 census, encompasses the city of Charleston and parts of four nearby rural counties and stretches south along the coast to include wealthy Hilton Head Island.
Republican Senator Tim Scott, who vacated the seat when he was appointed to the Senate, did not endorse a candidate.
Governor Nikki Haley appointed Scott to the Senate in December to replace Senator Jim DeMint, who resigned from office to head the Heritage Foundation, a conservative think tank.
Colbert Busch won the Democratic contest last month by a landslide, taking more than 95 percent of ballots cast. She touted her experience as director of sales for a shipping line and a leader in advocating science and math education in South Carolina.
Her brother is due to host two high-priced fundraisers for Colbert Busch's campaign this month in Washington and New York. Stephen Colbert is the host of the popular show "The Colbert Report" on cable TV's Comedy Central channel.
Her campaign has released internal polling that showed her leading Sanford by as much as 3 percentage points before Tuesday's Republican runoff. A Public Policy Polling survey released last week showed Colbert Busch leading Sanford with 45 percent favorability to Sanford's 34 percent favorability.
(Editing by David Adams and Will Dunham)


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President Bush is off to Beijing for the Olympics. In doing so, the White House has made it clear that while there, his purpose will primarily be to "show respect" to the Chinese people.
He will demonstrate this "respect" by avoiding dissidents and by not attending any worship services by faith denominations that suffer persecution by that country's Communist government. Rather than use his time to spotlight those struggling for freedom, he will be allowing himself to be part of a propaganda show.
Like many other tourists, he will be there to watch the athletes and to lend the good name of the American republic to the whitewashing of a despotic regime — still the world's largest tyranny — whose innumerable crimes have become a footnote to its successful pursuit of Western cash.
His behavior is proof that support for a belief that the cause of human rights ought to trump the conventional wisdom of the day about realpolitik and commerce is at a new low.
Unavoidable Comparison
Bush once seemed to base the entire foreign policy of his presidency on the notion of democracy promotion. But, as he kowtows to the Beijing regime, he is revisiting a role once played with gusto by two other Republican presidents a generation ago, when Richard Nixon and Gerald Ford embraced detente with the Soviet Union in the 1970s and similarly avoided meetings with that evil empire's internal critics.
While the two situations are not completely analogous, the death this past weekend of Aleksandr Solzhenitsyn, the Russian literary giant and symbol of resistance to communism, makes such comparisons unavoidable.
Nearly 20 years after the fall of the Berlin Wall, few young people had even heard of the 89-year-old writer. And for those that do, the image that many retain is that of the cranky old man who raged against the materialism of the West, as well as that of the Russia that emerged from the nightmare of communism. His books, while famous, are, with one exception, largely unread.
As Norman Podhoretz wrote in Commentary magazine in 1985, when Solzhenitsyn's anti-communism was still deeply relevant to contemporary politics, "The Gulag Archipelago is one of the most famous books ever written," but said few had actually read it. He allowed that A Day in the Life of Ivan Denisovich was widely read, but that the readership of Solzhenitsyn's works were, he said, generally "more reviewed than read."
His courage ought to inform the behavior of decent persons in the 21st and all those centuries that will follow.
And yet, Solzhenitsyn remains one of the most important persons of the 20th century. His courage ought to inform the behavior of decent persons in the 21st and all those centuries that will follow. His books did as much to bring down the most murderous regime of the modern age as the work of any other person or nation.
The publication of Ivan Denisovich made the suffering of the tens of millions imprisoned in Soviet slave labor camps real for a world that had denied they existed. The Gulag Archipelago documented in his unique style one of the greatest crimes in history and gave a voice to its hitherto silenced victims.
Even more dangerously, it pinned the blame for this evil not just on one man — Josef Stalin — as many liberals and Soviet sympathizers tried to do, but on his predecessor Vladimir Lenin and the entire belief system of socialism.
Having survived a long sentence in such a camp himself, Solzhenitsyn wrote Ivan Denisovich from his own memories, and then gathered the testimony of others to write Gulag and other important works.
Despite the constant threat of imprisonment and a return to the torture of the camps, he defied the Kremlin and the KGB, and spoke out against censorship. When he won the 1970 Nobel Prize for Literature, his acceptance address (delivered in absentia) warned an indifferent world that the duty of the artist was "not to participate in lies," and that even more, they had the power "to defeat the lie!"
Though it may not have seemed likely at the time, that is exactly what he, along with a generation of fellow dissidents and refuseniks that he helped inspire, did. Without his books, it is simply impossible to imagine that the struggle against the Communists, both inside and outside the country, would have succeeded as it eventually did. As much as any man ever has, Solzhenitsyn changed the world.
As with many great individuals, the writer had his faults. He did not understand the United States and made no attempt to do so in two decades on our shores after being forced into exile in 1974. While rightly calling for Americans to reject the moral relativism of the left and to resist the "spirit of Munich" that urged appeasement of Moscow, his cultural isolation also led him to denounce rock music and Western culture with as much bitterness as he did the gulag.
He morphed into a proponent of the values of tsarist Russia, authoritarian Russian nationalism and Orthodoxy, a stance that led him into indefensible stands on Serbian atrocities.
In exile, he also faced charges of anti-Semitism. Some critics rightly discerned an indifference and a lack of understanding of Jewish concerns, and a tendency to reflect the unpleasant traditions of Slavophile Russia, in which Jews were unfairly blamed for the rise of the Bolsheviks.
Yet, on the charge of Jew-hatred, most scholars and commentators have declared him not guilty, not least because he spent his whole life actively denying the accusation and was a steadfast supporter of the State of Israel. This question must also not be taken out of the context of the triumph of a movement for freedom for Soviet Jewry that his books and activism influenced and aided in an era when detente with the masters of the gulag was considered the most prudent course for the West.
Another Gulag
The point here is not just to honor him for his role in bringing down the Soviet Union, but to understand that his example must influence our attitude toward other human-rights abusers
Those who look away when confronted with the truth about places such as China, Tibet, Sudan and Iran cannot be allowed to do so without shame.
Despite the Olympics and the growth of capitalism in that nation, the laogai, the Chinese version of the Gulag Archipelago, still exists. Its prisoners — political dissidents, religious believers and others who earned the disfavor of Beijing — continue to suffer even as President Bush and other Americans spend their time there cheering at basketball games. The laogai has been documented, but sadly, it has yet to enter the lexicon or the conscience of the West the way Solzhenitsyn did with the gulag.
The legacy of the author of The Gulag Archipelago is that Bush and others who look away when confronted with the truth about places such as China, Tibet, Sudan and Iran cannot be allowed to do so without shame.
As Podhoretz wrote in 1985, the Russian forced everyone to confront "the terrible question" of our apathy in the face of evil by his example of being a lone, powerless man who stood up to the totalitarians and faced them down. So long as there are tyrants among us, that is an example we will need to honor and remember.


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On Friday, United Nations Secretary-General Ban Ki-moon called on Member States to sign, ratify or accede to various international treaties during this week's Treaty Event as part of the Organization's continuing effort to strengthen the rule of law around the world.
"The Treaty Event provides a distinct opportunity for States to reaffirm their continuing commitment to strengthen the rule of law at the international level," Mr. Ban said in his letter of invitation to Member States and their delegations while urging them "to join efforts to advance the universal application of the framework of internationally agreed upon norms and standards."
The annual treaty event, which was initiated in 2000, is an awareness-raising occasion by the UN Secretary-General, who is the depository of the 550 multilateral treaties that establish the rules of conduct for States. The event is intended promote participation in the treaty framework internationally and nationally.
Since it was established, the Treaty Event has resulted in 1,679 treaty-related actions, including signatures, ratifications, and accessions.
Only two treaties, however, have achieved 100 per cent participation while others have a broad participation but fall short of the goal of universal participation.
According to the UN, the rule of law is a principle of governance in which all persons, institutions and entities, including the State itself, are held accountable to publicly promulgated laws which are equally and fairly enforced, independently adjudicated, and consistent with international human rights standards.
This year's Treaty Event, entitled 'Strengthening the Rule of Law,' will be held from 24 to 26 September and from 1 to 2 October, to coincide with the General Assembly's high level meeting on the Rule of Law. This is a unique occasion for all Member States, non-governmental organisations and civil society represented at the highest level, to discuss and agree a forward looking agenda on strengthening the rule of law.
Additional links:
Source: UN News Centre / UNROL
The Brussels based United Nations Regional Information Centre for Western Europe - UNRIC provides information on UN activities to the countries of the region. It also provides liaison with institutions of the European Union in the field of information. Its outreach activities extend to all segments of society and joint campaigns, projects and events are organized with partners including the EU, governments, the media, NGOs, schools and local authorities.
United Nations Regional Information Centre for Western Europe (UNRIC Brussels)
Residence Palace, Rue de la Loi/Wetstraat 155, Block C2,7th and 8th floor, Brussels 1040, Belgium
Tel.: +32 2 788 8484 / Fax: 32 2 788 8485


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Browsing by Author "Lange, Sarah"
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Effect of Neofat on offspring sex ratios in Rambouillet and Suffolk sheep. Lange, Sarah E. (2011-05-10)Maternal diet and body condition are conceivably the most studied factors influencing sex ratio. The objective of this study was to determine if Neo-fat® influences offspring sex ratio in Rambouillet and Suffolk sheep. ...